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, 25 (2), 360-6

Beta-N-methylamino-L-alanine Enhances Neurotoxicity Through Multiple Mechanisms

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Beta-N-methylamino-L-alanine Enhances Neurotoxicity Through Multiple Mechanisms

Doug Lobner et al. Neurobiol Dis.

Abstract

The idea that the environmental toxin beta-N-methylamino-l-alanine (BMAA) is involved in neurodegenerative diseases on Guam has risen and fallen over the years. The theory has gained greater interest with recent reports that BMAA is biomagnified, is widely distributed around the planet, and is present in the brains of Alzheimer's patients in Canada. We provide two important new findings. First, we show that BMAA at concentrations as low as 10 muM can potentiate neuronal injury induced by other insults. This is the first evidence that BMAA at concentrations below the mM range can enhance death of cortical neurons and illustrates potential synergistic effects of environmental toxins with underlying neurological conditions. Second, we show that the mechanism of BMAA toxicity is threefold: it is an agonist for NMDA and mGluR5 receptors, and induces oxidative stress. The results provide further support for the hypothesis that BMAA plays a role in neurodegenerative diseases.

Figures

Figure 1
Figure 1
BMAA alone does not induce significant toxicity until a concentration of 1 mM. Bars show % neuronal cell death (mean ± SEM, n=8–16) quantified by measuring release of LDH, 24 hrs after the beginning of the exposure to BMAA. * indicates significant toxicity, P < .05 (one-way ANOVA followed by the Bonferroni t-test).
Figure 2
Figure 2
(a) BMAA induced toxicity is partially blocked by the NMDA receptor antagonist MK-801. Concentration used was: 10 µM MK801. Bars show % neuronal cell death (mean ± s.e.m., n=12–16) quantified by measuring release of LDH, 24 hours after the beginning of the insult. * indicates significant difference from control injury, P < 0.05 (Student’s t-test). BMAA mediated 45Ca++ uptake is blocked by MK-801. (b) 45Ca++ uptake was measured during a 1 hour exposure to BMAA. Bars show % control 45Ca++ uptake (mean ± s.e.m., n=16). * indicates significant difference from BMAA or NMDA alone, P < 0.05 (Student’s t-test).
Figure 3
Figure 3
BMAA has NMDA receptor agonist activity in CNS neurons. (a) Current activated by BMAA at various concentrations in a cultured cortical neuron. Concentrations used were: 10 – 3000 µM BMAA, 50 µM glycine,. (b) Concentration dependence of BMAA-activated current. Note that concentrations in the low micromolar range elicited measurable currents. (c) Current elicited by the application of BMAA is blocked by the NMDA receptor antagonist APV. Concentrations used were: 3000 µM BMAA, 500 µM APV. (d) Bars indicate current (mean ± s.e.m.; n = 4) activated by 3000 µM BMAA, in the absence and presence of 500 µM APV. * indicates significant difference from BMAA alone, P < 0.05 (Mann-Whitney test).
Figure 4
Figure 4
(a) BMAA induced toxicity occurs through multiple mechanisms. Concentrations used were: 10 µM MK-801, 50 µM MPEP, 100 µM trolox. Bars show % neuronal cell death (mean ± s.e.m., n=24–28) quantified by measuring release of LDH, 24 hrs after the beginning of the insult. * indicates significant difference. (b) BMAA induced oxidative stress is not attenuated by MK-801 or MPEP, but is blocked by trolox. 5-(and –6)-carboxy-2’7’-dichlorodihydrofluorescein diacetate (10 µM) was added to the cultures during a 3 hour exposure to BMAA. Bars show % control fluorescence (mean ± s.e.m., n=24–28). * indicates significant difference, P < .05 (one-way ANOVA followed by the Bonferroni t-test).

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